Management of colorectal cancer: A role for genetics in prevention and treatment?

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Abstract

Colorectal cancer remains one of the most common cancers in the Western world and amongst the top three causes of cancer morbidity and death. Cancer is caused by genetic mutations, but currently there is little use of genetic information in the clinic with the exception of establishing germline mutations for the uncommon predisposing syndromes. Rapid advances in technologies allowing high throughput analysis of germline and somatic mutations raises the possibility that genetics will find a major role in the clinic distinguishing individuals at low to high risk of cancer, allowing early intervention and stratification of cancers based on mutational pathways for therapeutic interventions. In the future, this will lead to treatment regimes tailored to the individuals and their tumor. Here, we summarize the genetics underlying colorectal cancer and the future role of genetics in prevention, diagnosis, classification and treatment.

Introduction

Colorectal cancer (CRC) remains the second commonest cause of cancer-related mortality and morbidity in the Western world [5]. In the UK, it is the third commonest cancer, after lung and breast, with approximately 35,000 new cases diagnosed each year. Worldwide, over a million cases of CRC were diagnosed in 2002, accounting for 9% of all new cancer cases, with the incidence being much higher in industrialized countries than in Africa and Asia [9].

Cancer of the large bowel is a disease of old age with more than 80% of cases arising in those aged 60 years or over. Cases arising in younger patients are usually associated with familial syndromes and underlying genetic predisposition. Incidence is equal between the sexes up to the age of 50, but in older age groups the incidence is higher in males. Historically, the left side of the colon (and rectum) accounted for the majority CRCs, but in the western world, this preponderance has fallen from 75% in the mid-twentieth century to just over 50% in recent years [49].

With advances in surveillance, surgical techniques, adjuvant therapies and cancer genetics, 5-year survival in patients diagnosed with CRC has improved over the last 30 years from around 22% to 47%. However, the overall survival remains disappointing, with more than 16,000 CRC-related deaths in the UK in 2004 alone [9]. This paper reviews and asks whether the latest advances in genetics have a role in prevention and treatment.

Section snippets

The genetics of colorectal cancer: the adenoma–carcinoma sequence

Cancer is a genetic disease caused by germline (inherited) and somatic (acquired) mutations and epimutations. Many of the genes for Mendelian cancer syndromes, including those for CRC, have now been identified, and these studies have provided numerous insights into the common forms of tumorigenesis, particularly in the sporadic form of cancer. A cancer, such as CRC, develops by a process of somatic evolution with genomic instability identified as an important event in the multi-step progression

Classification of colorectal cancers by mutational pathways

Genomic instability is an important event in the multi-step progression of cancer. To date, two apparently independent genetic pathways of tumorigenesis have been characterized in sporadic CRC: chromosomal instability (CIN) and microsatellite instability (MIN) [36], [60]. Cancers that develop via the CIN pathway show chromosomal abnormalities such as aneuploidy, loss of heterozygosity (LOH) and sequential inactivation of tumor suppressor genes (TSGs) such as APC (5q), p53 (17p) and SMAD4 (18q)

Classification of colorectal cancers by single-nucleotide polymorphism array analysis

If a robust classification system is to be developed to describe the genetic changes that underlie the biology of CRC development and allow subdivision for diagnostic, prognostic and treatment purposes, then these events need to be defined simultaneously, throughout the genome and at high resolution. The very recent advent of single-nucleotide polymorphism (SNP) arrays provides a powerful tool for establishing a number of genetic events that have occurred in a given tumor [18]. SNPs represent

Staging of tumors by single-nucleotide polymorphism array analysis

Staging of CRC aims to provide prognostic stratification in patients who have undergone surgery. In 1932, Cuthbert Dukes described a staging system based on invasion through the bowel wall and lymph node involvement. This system has been modified through the years and remains a highly accurate predictor of outcome.

The corrected 5-year survival of patients with Dukes A and B cancers is high (up to 95% and 60–80%, respectively), but falls dramatically to only 35% in patients with Dukes C cancers

A role for genetics in routine clinical practice: screening for predisposition

Genetic testing for predisposition to cancer has become a standard component of clinical practice over the last few years. The majority of testing for inherited germline mutations is performed in the context of family history and our current knowledge of the hereditary cancer syndromes. The implication for the individual is an increased risk of developing cancer from the second decade of life and that this risk increases with age. The clinical presentations, genetics and the clinical practices

A role for genetics in routine clinical practice: targeting chemotherapy to the individual

The genetic background of an individual or the mutation profile/ tumorigenic pathway of their cancer is not currently taken into account when chemotherapy is given. As a result, patients are often exposed to the same chemotherapy regimens despite having very different tumors in terms of genetics. In addition, individuals may carry protein variants that markedly differ in their capacity to metabolize or clear drugs from the body. Such factors could be detrimental to patient's survival, as no

Concluding remarks

In order to improve the survival of CRC patients, it is essential that we are able to discriminate cancers in terms of their tumorigenic pathway and mutational profile to provide information for stratification for therapeutic intervention. Similarly, it is important to establish if metastatic lesions survive and grow, thanks to the same genetic aberrations as the primary tumor or require further genetic mutations. An arsenal of drugs that specifically targets a cancer's unique genetic defects

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